Hindawi Publishing Corporation
Neural Plasticity
Volume 2016, Article ID 3425908, 11 pages
http://dx.doi.org/10.1155/2016/3425908
Review Article
Structural, Synaptic, and Epigenetic Dynamics of
Enduring Memories
Ossama Khalaf and Johannes Gräff
Laboratory of Neuroepigenetics, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL),
1015 Lausanne, Switzerland
Correspondence should be addressed to Johannes Gräff; johannes.graeff@epfl.ch
Received 18 September 2015; Revised 23 November 2015; Accepted 24 November 2015
Academic Editor: Pablo Munoz
Copyright © 2016 O. Khalaf and J. Gräff. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Our memories are the records of the experiences we gain in our everyday life. Over time, they slowly transform from an initially
unstable state into a long-lasting form. Many studies have been investigating from different aspects how a memory could persist for
sometimes up to decades. In this review, we highlight three of the greatly addressed mechanisms that play a central role for a given
memory to endure: the allocation of the memory to a given neuronal population and what brain areas are recruited for its storage;
the structural changes that underlie memory persistence; and finally the epigenetic control of gene expression that might regulate
and support memory perseverance. Examining such key properties of a memory is essential towards a finer understanding of its
capacity to last.
1. Introduction
Based on experience, memory is the capacity of an individual
to acquire, store, and retrieve information. The physical
substrate of such memories in our brains is known as memory
trace or as first coined by the German biologist Semon (1859–
1918) as “engram” [1–3]. One of the fundamental questions
in memory research is how the experiences that we acquire
transform into engrams that persist over time. It is generally
acknowledged that the records we form from our daily
experiences are not stored instantaneously but rather retained
in an initially labile state that gradually transforms into a
more stable trace or engram that is characterized by resistance
to disruption [4–6]. Although this view has been challenged
by the reconsolidation hypothesis, stipulating that even a
stably stored memory could become transiently sensitive to
disruption upon recall [6, 7], it is evident that not all forms of
memories are amenable to disruption [8]. This is particularly
relevant for strong memories, induced by an intensive training protocol, and long-lasting forms of memories, ranging
from several weeks to months [9, 10] in age. Based on these
grounds, but notwithstanding several studies testifying to
the amenability of even long-term memories to disruption
[11, 12], in this review we focus on 7-day-old—and older—
memories as being remote and with the potential to endure,
and we outline three mechanisms that might contribute to
such endurance: first, memory allocation and storage; second,
structural neuronal changes; and third, nuclear epigenetic
dynamics (Figure 1).
Memory allocation refers to an early process by which
certain neural circuits are assigned to stow a specific memory
and what might favor the allocation of a memory into a
specific population of neurons over others. In this review,
we focus on some of the well-described elements that govern
such allocation; still it is clear that we are only at the beginning
of understanding the entire process of memory allocation,
and many more aspects thereof remain to be identified. Once
allocated, the question of where the memory is stored and
what brain regions upkeep the memory is another one of
utmost importance. The whereabouts of a specific memory
is thought to be dependent on how old this memory is.
The more nascent it is, the more it will be hippocampaldependent, but as it matures it will change such dependence
to higher cortical regions [13, 14]. Here, we describe brain
areas that have been defined to be essential for the support
of a long-lasting memory.
2
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HPC
Memory allocation
PFC
AMY
PFC: prefrontal cortex
HPC: hippocampus
AMY: amygdala
Structural plasticity
Epigenetic regulation
Histone PTMs
Me
Me
DNA methylation Me
Acetylation
Phosphorylation
Figure 1: Schematic illustrating three essential mechanisms that might contribute to remote memory storage and thus memory endurance
in the (rodent) brain, which are discussed in this review. First, during memory allocation, learning induces the activity of a specific
subpopulation of cells—likely spread across different brain areas—which will become recruited into the memory trace. The amygdala (AMY),
the hippocampus (HPC), and the prefrontal cortex (PFC) are known to be activated during memory allocation (for details see text). Second,
in cells allocated to a specific memory—also known as the memory engram [1–3]—structural changes at the level of dendritic spines have
been demonstrated by several studies. These changes are exclusive to the cells of the memory trace or engram (red) but not observed
in other cells (grey) [53]. Third, memory engram cells are also likely to be characterized by epigenetic changes, such as posttranslational
modifications (PTMs) on histone proteins, and methylation of the DNA, the core chromatin constituents. Note, however, that such engramspecific engagement of epigenetic mechanisms remains to be experimentally demonstrated.
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Furthermore, many neuroscientists believe that memories are encoded into neurons as structural changes in
synaptic connections. Indeed, such structural plasticity is
under comprehensive study in order to understand how
brain circuits are modifying themselves in terms of number
and strength of synaptic connections that correlate with the
persistence of a memory [15–17]. We discuss these physical
changes in synapses and their potential to support enduring
memories.
Lastly, we also discuss the epigenetic modifications that
are associated with long-lasting memories. We shed light on
such modifications to the DNA or the histone tails that could
lead to a cascade of changes in gene expression, a key feature
of long-term memories [18], and which might thereby be
able to assist memories to persist throughout the life of an
individual.
2. Memory Allocation and Storage
Once formed, memories gradually transform from an initially
vulnerable state to a more permanent state that is increasingly
persistent to disruption. Such process of postexperience
memory stabilization was first described by Müller and
Pilzecker referring to it as “memory consolidation” [4, 5].
Later, two different types of memory consolidation have been
distinguished: cellular/synaptic and systems consolidations.
Cellular consolidation is a rather fast process taking place
within the first few hours following learning and necessary for
the initial stabilization of memories in hippocampal circuits
[13]. In contrast, the systems consolidation process is slower
and involves a time-dependent, gradual reorganization of
the brain regions that support the memory, with the memory dependence shifting from the hippocampus to cortical
regions [14]. This led to the contemporary view of systems
consolidation which states that the hippocampus (HPC) is
merely a temporary store for new information, while its
permanent storage depends on largely distributed cortical
networks [14].
In this section, we review what molecular and cellular
events govern memory allocation in or to a certain neuronal
population and then what brain regions support long-lasting
memory storage.
2.1. Memory Allocation. By definition, memory allocation
is the set of processes that determine where information
is stored in a particular neural circuit [19]. Several studies
showed that such allocation is not random but rather dependent on specific molecular mechanisms [20–22]. In one of
these studies [20], using a viral vector Han et al. artificially
increased the levels of CREB (cAMP responsive elementbinding protein), a transcription factor important for the
stability of synaptic potentiation and memory [23] in neurons
of the lateral amygdala (LA), a subcortical brain structure
implicated in emotional memories [24, 25], in mice. Twentyfour hours after a tone fear conditioning training, the mice
were tested for the tone and sacrificed 5 min later. Using
cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH), LA neurons transfected
with CREB—identified by its GFP fluorescent tag—were
3
found to be three times more likely than their neighboring
nontransfected cells to express activity-regulated cytoskeletal
(Arc), a gene required for synaptic function and memory
[26, 27]. This suggests that CREB levels bias neurons to
become part of the engram and to be encoded by the tone
conditioning in the amygdala.
In a subsequent loss-of-function study, cells that were
virally transfected with CREB in the same behavioral
paradigm were ablated using diphtheria toxin receptor
(DTR). In this system, the expression of the DTR is inducible
by the Cre-recombinase, which is also found in the same
viral construct, making all the cells that receive the construct
eventually express the DTR. Following the tone test (24 h
after training), the mice were injected with the diphtheria
toxin (DT) that will only interact with the cells expressing
the DTR and kill them. The experimental group (CREB viral
vector transfected and DT injected) showed a significant
impairment in tone conditioning when tested 2 days after
the DT injection [21]. Similar results were obtained using
a different approach that allows for reversible neuronal
activation instead of permanently killing the cells [22]. There,
the Drosophila allostatin inhibitory receptor was delivered to
the LA through the same viral construct providing CREB,
and pronounced amnesia for tone conditioning was obtained
as a result of inactivating these cells by allostatin peptide
treatment. This amnesia was reversed upon retesting the mice
one day later without the allostatin peptides demonstrating
the reversibility of the allostatin effects and the link between
activity in the CREB cells and recall [22]. Despite the exclusive
focus on CREB in the previous studies, the convergent
findings using three different strategies strongly support its
important role in memory allocation in the amygdala.
Another influential factor that determines the allocation
process appears to be neurogenesis in the dentate gyrus (DG).
Using 5-bromo-2󸀠 -deoxyuridine (BrdU), a permanent stain
that intercalates with dividing DNA allowing the tracing of
newly born neurons, a recent study showed that 4- to 8week-old DG neurons are preferentially recruited after spatial
learning [28]. In contrast, 2-week-old neurons integrated
with lower efficiency and 1-week-old neurons did not integrate at all [28]. In line with a recent study showing that
4-week-old (but not 1-week-old) neurons have the essential
synaptic structure and physiology to support the appropriate
connections with hippocampal circuits [29], this suggests that
the timing of neuronal development relative to training is
indeed vital in the memory allocation process. Nevertheless,
the nature of memory allocation processes that take place in
brain areas devoid of neurogenesis and outside the amygdala
remains to be determined.
2.2. Memory Storage. After the initial allocation of a memory
to a specific neural circuit begins the more prolonged process
of systems consolidation that involves gradual reorganization
of the brain regions that support memory formation and
storage [13, 14]. Classical studies characterizing memory
loss in patients with lesions of the medial temporal lobe
(MTL) [30, 31] revealed that the hippocampus serves as a
temporary store for new information, but that permanent
information storage depends on a broadly distributed cortical
4
network [14]. These human data are indeed consistent with
observations that hippocampal lesions in the first week after
training, but not thereafter, disrupt contextual fear memories
in rats, and thus, maintaining a proper hippocampal trace is
crucial to establish remote memories in the cortex [32]. From
more refined studies, several molecules have in the meantime
been identified that maintain the hippocampal trace of a
memory in the days following training for the persistence
into a remote memory [33, 34] (for a more detailed overview
of other molecules that are involved in memory storage,
but that have not been specifically assessed for remote
memory storage, the reader is referred to [19]). For instance,
when NMDA (N-methyl-D-aspartate) receptor (NMDAR)
function was inducibly suppressed in the CA1 region in the
week following the training of two hippocampal-dependent
tasks (Morris Water Maze and contextual fear conditioning),
remote memory formation for these tasks was blocked.
However, when done at later time points, the suppression
of the NMDAR function did not affect the remote memory
formation [33]. Similar results were obtained when levels
of 𝛼-calcium/calmodulin kinase II (𝛼-CaMKII), a signaling
enzyme mainly expressed in the excitatory neurons of the
forebrain and essential for neuronal plasticity [35], were
altered [34]: overexpressing a dominant-negative form of
𝛼-CaMKII in the week after training, but not afterwards,
blocked the formation of remote contextual fear memories
[34]. Together, these results support the importance of the
HPC, especially during the first week following encoding, for
memory consolidation in cortical networks and furthermore
suggest that there is a crucial week-long window during
which normal hippocampal activity is needed for the memory to be consolidated.
However, several studies found that cortical regions are
also implicated in the initial phase of memory formation [36–
39], thus challenging the idea that the HPC is solely involved
in this process. In one of the recent studies in this regard
[38], real-time optogenetic inhibition of excitatory medial
prefrontal cortex (mPFC) neurons during contextual fear
conditioning showed that such temporally precise inhibition
impaired the formation of long-term associative memory,
tested 30 d after of acquisition [38]. In another recent study
[39], using a doxycycline-inducible mouse line (TetTag) to
tag the activated neurons [40], optogenetic stimulation of the
activated neural population during contextual fear memory
training in the retrosplenial cortex (RSC), a cortical region
implicated in episodic memories and emotional associations
[41–44], was sufficient to produce fear memory retrieval even
when tested until 2 d after acquisition [39]. These results
are in line with previous studies [36, 37] showing that the
PFC is critically involved in memory encoding and that
its inactivation by local infusion of NMDAR antagonist
could block contextual memory acquisition in mice [36] and
learning of new paired-associates in rats [37].
In another intriguing study, Lesburguères et al. used a
social transmission of food preference (STFP) test, where an
associative olfactory memory develops after a study animal
(observer) learns about the safety of a certain food (novel
odor for the observer) from an interaction session with
Neural Plasticity
another animal that has already tasted the food (demonstrator). Then the observer shows reduced fear towards this novel
food upon the first encounter and significant consumption
thereof. The authors first showed that the acquisition of such
food preference memory is dependent on the orbitofrontal
cortex (OFC) only for 30-day-old remote memory, but not
for recent memory (24 h after training), and that for the first
period after training (7 d) it is mainly HPC-dependent [45].
Nevertheless, the authors then went on to show that there is
an intricate interplay between the HPC and the OFC for such
memory to endure. Using the excitatory glutamate receptor
antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) to
block the activity of the OFC during the 2-week period
following training, an unexpected memory loss to a novel
odor test was observed 30 d later. Likewise, inactivating the
OFC immediately before training blocked the memory after
30 d, and not after 7 d, indicating that early cortical activity is
required for subsequent stabilization of such memory [45].
Beyond memory formation, several studies investigated
the role of extrahippocampal structures in remote memory
storage, from which the anterior cingulate cortex (ACC)
emerges to play a key role at least in remote contextual fear
memory storage [46–49]. Thus, lidocaine-mediated pharmacological inactivation of the ACC disrupts the retrieval
of remote contextual fear memory in mice 18 d and 36 d
after training, while inactivating the prelimbic cortex (PL)—a
region located near the ACC in the mPFC—at the same time
points did not disrupt the very same memory [46]. Similarly,
the lidocaine-mediated inactivation of the PFC and the ACC
was shown to impair remote spatial memory retrieval when
tested 30 d after acquisition [47]. These results are in line
with previously reported data from a study using noninvasive
functional brain imaging to examine the metabolic activity
of different brain regions underlying spatial discrimination
memory storage in mice [48]. In this study, increased
metabolic activation in the frontal cortex, together with the
recruitment of the ACC and temporal cortices, was observed
25 d—but not 5 d—after acquisition [48]. Together, these
findings indicate a high level of involvement of cortical areas
during the retrieval of remote memories, postulating these
areas to be vital structures for remote memory storage.
Finally, from a reconsolidation point of view and how
memory storage could affect such process, it has been
previously demonstrated that infusing anisomycin (ANI), a
protein synthesis inhibitor, to the dorsal HPC (dHPC) or
the ACC after contextual fear memory recall (45 d or 30 d
after acquisition, resp.) disrupts the memory when tested 1 d
after anisomycin treatment [11, 49]. Collectively, these results
highlight an equal importance of hippocampal and cortical
regions in remote memory reconsolidation, which suggest
that probably the process of memory formation and storage
does not depend solely on a single brain area but is more
distributed among different structures that share the upkeep
of the trace.
3. Structural Changes
Amongst many aspects that categorize a memory to be
remote is persistence, yet how this property is achieved
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is still enigmatic. The strength and number of synaptic
connections that are formed after an experience offer one
possible explanation as to how remote memories could
endure and last throughout life [18]—since we know that such
processes—such as increased dendritic spine density—are
indeed implicated in 1-day-old memories [15, 50, 51]. In this
section, we shed light on the structural changes that modify
the connectivity of brain networks and that might underlie
remote memory perseverance.
A few years ago, Restivo and colleagues used contextual
fear conditioning as a behavioral paradigm to show that
recent and remote memory formation trigger region-specific
and time-dependent morphological changes in hippocampal
and cortical networks of mice [16]. Right after fear conditioning, there was a significant increase in spine density in the
CA1 field of the hippocampus compared to the naı̈ve or even
pseudoconditioned groups. 36 days later, in contrast, this
increase in spine density had developed sequentially when
it reached the cortical regions, specifically the ACC. Thus,
hippocampal plasticity per se is seemingly crucial in driving
the structural changes that were observed at a remote time
point, yet its role was merely time limited, an observation
that was recently confirmed using time-lapse two-photon
microendoscopy [52]. To further prove this assumption,
a hippocampal lesion was generated early at the day of
conditioning, where it abolished the growth of significant
spine density in the ACC (36 d after training) compared to the
sham group [16]. In contrast, when this lesion was introduced
at a later time point (24 days after conditioning), it did not
prevent the spine density changes in the ACC neurons. The
detected structural changes in either region were directly
correlated to the strength of the conditioned memory: an
absence of these structural changes in the hippocampal or the
cortical regions was accompanied by memory impairments
for recent and remote memories, respectively. This is in line
with a recent demonstration that such increase in synaptic
density and plasticity occurs exclusively in engram cells, but
not in nonengram cells, in the DG 24 h after encoding [53].
Importantly, such structural remodeling in hippocampal
and cortical regions is essential for memory stabilization
and afterwards for remote memory expression. The spine
growth at the hippocampal neurons is important at an early
time point after conditioning, yet this importance starts to
fade with time, when a more permanent trace is formed
in the cortex [17], as illustrated by the following study. To
inhibit the structural changes that occur in the cortex, a
transcription factor that is known to negatively regulate
spine growth, myocyte enhancer factor 2 (MEF2), was
overexpressed through a viral vector to increase the MEF2dependent transcription in ACC neurons at 2 different time
points, either 1 day or 42 days after conditioning. At the earlier
time point, the stabilization of the conditioned memory
and the associated increase in spine growth was blocked,
whereas no effect was observed at the later time point [17].
This suggests that the increase in spine growth at the ACC
following conditioning happens in a time-dependent manner
and that it is central for the stabilization and persistence of
such memory.
5
In contrast to the abovementioned studies, another study
showed a rapid formation of new spines in the motor cortex
of mice following a novel motor skill learning task [54]. Using
in vivo superficial dendrites imaging, they demonstrated that
there is an immediate formation of spines in the motor
cortex following a novel motor learning task (within 1 h after
learning initiation) and that these spines are preferentially
stabilized upon subsequent training and endure long after
training stops (up to 120 d) [54]. This suggests that the early
cortical structural changes during motor learning and the
subsequent stabilization over months subserve as long-lasting
structural basis for memory maintenance and persistence
of a motor skill. Similarly, a more recent study reported
that the encoding of a long-term episodic memory itself
elicits early structural changes in neocortical regions. In this
study, structural plasticity in the mPFC was significantly
increased 1 h following contextual fear conditioning [38]:
investigating the morphology of individual dendritic spines
on mPFC pyramidal neurons revealed that the ratio of the
thin spines to mushroom spines was significantly increased
following conditioning. This suggests that dendritic spine
plasticity in the mPFC circuit also contributes to memory
encoding, which is surprising as the remodeling of the cortex
was traditionally thought to be limited to the later stages of
memory processing that promote remote memory storage
[55]. Further investigations are now needed to have a better
understanding of these structural changes and how they are
employed to serve memory lasting or extinction (Box 1).
4. Epigenetic Regulation
Remote memories persist throughout the life of individuals,
whereas the protein molecules that may subserve these
memory traces are thought to turn over on the order of
days [56]. To address such unanswered questions dealing
with the molecular basis for a lifelong memory, it has been
proposed by Crick (1916–2004) in 1984 and later on by
the molecular biologist Holliday (1932–2014) in 1999 that
epigenetic mechanisms—particularly DNA methylation—
could partly explain the persistence of memories over a
lifetime [57, 58]. Epigenetics has long been heralded as a
stable and self-perpetuating regulator of cellular identity
through establishing persistent and heritable changes in gene
expression across cell divisions [20]. Although the nervous
system is essentially composed of nondividing cells, the
recent decade has shown that epigenetic mechanisms could
nevertheless play a fundamental role in forming lasting
memories.
Commonly, DNA is packaged into chromatin through its
wrapping around octamers of histone proteins. Chromatin
can exist either as heterochromatin or as euchromatin: heterochromatin is characterized by condensed chromatin and
subsequent transcriptional repression, whereas euchromatin
is characterized by a relaxed chromatin state that allows the
transcriptional machinery to access the DNA for gene expression [59]. Apart from short interfering RNA molecules that
mediate posttranscriptional gene silencing [60] and induce
epigenetic changes in gene expression via modifications of
chromatin [61], the switch between both states of chromatin
6
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In addition to remote memory storage, memory extinction—in the case of remote fearful memories—also alters structural spine
plasticity. For instance, remote memory extinction was found to diversely alter the spine density and spine size in the ACC and
infralimbic cortex (ILC) in mice [78]: extinction of a 31-day-old contextual fear memory decreased the density of dendritic spines
in the ACC significantly, but not the size. In contrast, the spine density remained elevated in the ILC but the size of spines decreased
dramatically. The persistence of spine enlargement in the ACC upon extinction could be essential to warrant that the consolidated
fear and the extinction memory traces are kept in a dormant state to allow their reactivation long after training. This may indicate
that the extinction per se partially remodels the neuronal network supporting the original memory representation. Intriguingly,
another study described the opposite effects of fear conditioning and extinction on dendritic spine remodeling in the frontal
association cortex (FrA) of rats [79]. Using two-photon microscopy to examine the formation and elimination of postsynaptic
dendritic spines of the FrA, the cued fear conditioning caused rapid and long-lasting spine elimination that was significant over 2
and 9 days. After 2 days of extinction training, the spine formation was significantly increased and its degree predicted the
effectiveness of the extinction to reduce the conditioned freezing response. These results paradoxically conclude that fear
conditioning mainly promotes spine elimination, whereas extinction essentially induces spine formation. More studies in different
brain areas will be of high interest to corroborate these findings.
Box 1: Recent insights into structural plasticity and remote fear memory extinction.
is governed by two major epigenetic modifications: DNA
methylation and posttranslational modifications (PTMs)
on histone tails. DNA methylation refers to the covalent
addition of a methyl group to the cytosine base by DNA
methyltransferases (DNMTs), while PTMs are the addition
and removal of chemical moieties to histone tails, which
are dynamically regulated by chromatin-modifying enzymes
[22]. These modifications include—but are not limited to—
histone acetylation, phosphorylation, and methylation [62]
(see Tweedie-Cullen et al., for a complete overview of recently
identified PTMs in the brain [63]). Both types of epigenetic
modifications are associated with learning and memory, and
many recent studies have shown that these epigenetic changes
could support memory formation and maintenance through
a cascade of specific changes to gene expression including
enduring memories.
4.1. DNA Methylation. The first study to investigate the
potential role of DNA methylation in regulating memory
formation by Sweatt and colleagues showed that Dnmt gene
expression is upregulated in the adult rat hippocampus
following contextual fear conditioning and that its inhibition
blocks memory formation [64]. Accordingly, fear conditioning was associated with an upregulation of mRNA levels
of the DNMT subtypes that are responsible for de novo
methylation, DNMT3A and DNMT3B, in the CA1 region
30 min after training. Then, to show that the hippocampal
DNMT activity is necessary for memory consolidation,
DNMT inhibitors—5-azadeoxycytidine (5-AZA) or zebularine (zeb)—were locally infused right after the training,
where they abolished the freezing response of the injected
group 24 h after (test day 1). Interestingly, when retrained
immediately after test day 1 and retested 24 h later (test day
2), the DNMT inhibitor-treated group showed significantly
higher freezing than on test day 1, and when retrained
and retested 24 h later (test day 3), they showed equivalent
freezing to the vehicle-treated group. But when 5-AZA was
infused 6 h after training and animals were tested 18 h later
(24 h after training), the inhibitor-injected group displayed
normal fear memory indicating that the effect of DNMT
inhibition is merely due to blocking consolidation and not
due to any other effects on the retrieval or the performance of
the animals [64]. These experiments suggest that the transient
inhibition of DNMT in the hippocampus following training
blocks memory consolidation in a resilient manner that could
be reverted as soon as the inhibitor clears off and that the
necessary DNA methylation states for consolidation could be
reestablished.
In a follow-up study, Miller et al. found a rapid increase
in methylation of a memory-suppressor gene in the hippocampal CA1 region 1 h after contextual fear conditioning.
Using quantitative real-time PCR, the methylation levels
of protein phosphatase 1 (PP1), a memory-suppressor gene
that is suggested to promote memory decline [65], were
dramatically higher in the fear-conditioned group compared
to the control group. This increase in methylation was
associated with lower levels of PP1 mRNA, yet the increase
in methylation was attenuated and associated with a twofold
increase in the mRNA levels when 5-AZA was infused locally
1 h after training. Conversely, a demethylation of a memorypromoting gene was found in the CA1 region 1 h after contextual fear conditioning. The demethylation of reelin, a gene
that enhances long-term potentiation and the loss of function
of which results in memory formation deficits [66, 67], was
pronounced in the trained group with its mRNA levels being
significantly higher than the control group. DNMT inhibition
using 5-AZA led to further demethylation of reelin and even
higher levels of its mRNA. These data suggest that the DNA
methylation is dynamically regulated and that it is a crucial
step in memory formation.
Importantly, cortical DNA methylation also seems to
support remote forms of memories [68]. The cortical DNA
methylation of the memory-suppressor calcineurin (CaN,
also known as Ppp3ca), a gene that downregulates pathways
supporting synaptic plasticity and memory storage, was
investigated using methylated DNA immunoprecipitation
(MeDIP) in rats. CaN’s cortical DNA methylation persisted
for at least 30 d after contextual fear conditioning, and its
mRNA levels were significantly reduced in the trained group
2 h after retrieval 30 d after training. Importantly, when
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the NMDA receptor antagonist (AP5) was infused into
the dorsal hippocampus (CA1) just before training, CaN
methylation in the dorsal medial prefrontal cortex (dmPFC)
7 d after training was blocked, indicating that a single
hippocampus-dependent learning experience is sufficient to
drive lasting, gene-specific methylation changes in the cortex.
Moreover, intra-ACC infusions of DNMT inhibitors (5-AZA
or zeb or RG108) 30 d after training disrupted fear memory
and were associated by a significant reduction in the CaN
methylation levels. However, the infusion of these inhibitors
1 d after training had no effect on fear memory 30 d later
[68]. These results indicate that cortical DNA methylation
is indeed triggered by a learning experience, and most
importantly, its perpetuation supports long-lasting, persistent memories. More detailed studies including investigating
DNA methylation changes on a genome-wide scale or within
engram-bearing cells are clearly warranted to deepen our
knowledge of the implication of these changes in remote
memory storage.
4.2. Histone PTMs. Newly formed hippocampus-dependent
memories need to be stabilized into a long-lasting ACCdependent memory trace [46, 69, 70]. Several studies demonstrated that changes in gene expression in both brain regions
accompany such stabilization [46, 47]. This differential gene
expression has recently been associated with epigenetic modifications in terms of histone PTMs [71]. Using a novel object
recognition task on mice, serine (S) 10 phosphorylation on
histone (H) 3, lysine (K) 14 acetylation on H3 as well as H4K5
acetylation, and H3K36 trimethylation in the PFC associated with remote (7 d after training) memory consolidation.
Importantly, the doxycycline-inducible selective inhibition of
the memory-suppressor gene PP1 in a transgenic mouse line
showed improved remote memory performance accompanied by increased histone PTMs. In contrast, blocking the
occurrence of these PTMs using a cocktail of inhibitors targeting the epigenetic enzymes responsible thereof impaired
remote object memory, suggesting that these histone PTMs
are essential for memory consolidation and retention. Finally,
these histone PTMs were increased in the promoter region
of Zif268—an immediate early gene important for memory
formation and storage [72]—and its expression levels shift
from the hippocampus to the PFC as the memory matures
[71]. This study shed light on the spatiotemporal dynamics
of these histone PTMs in the hippocampus and cortex
and demonstrated that they could act as molecular marks
subserving memory consolidation—at least up to 7 d after
training.
Similar results were obtained for memory consolidation
of social transmission of food preferences [45]. There, associative olfactory memory was linked to a marked increase in
H3 acetylation in the OFC 1 h after training, but such increase
disappeared upon inactivating the OFC using tetrodotoxin
or CNQX. Additionally, increasing the OFC histone acetylation by infusing HDAC inhibitors (sodium butyrate or
trichostatin A) was associated by an increase in memory
robustness at the remote time point (30 d) [45]. Together,
these results stipulate that this cortical epigenetic mark
observed very early during training might be essential for
7
tagging these neurons to allocating them to the long-term
olfactory memory and that thereafter these neurons will
participate in the system consolidation process driven by the
HPC-OFC circuitry in order to help this memory to endure.
It would be highly interesting to repeat this study with CREBtransfected OFC neurons in order to test this hypothesis.
In addition to histone PTMs, a recent study by Zovkic et
al. has shown that a variant of histone H2A (H2A.Z) is actively
exchanged in the hippocampus and cortex in response to fear
conditioning in mice [73]. H2A.Z is known to be associated
with nucleosomes adjacent to the transcription start site
(TSS) of a gene, and its presence has been strongly linked
to dynamic changes in gene expression [74]. To investigate
its effect on transcriptional changes associated with learning,
chromatin immunoprecipitation (ChIP) was used. Binding of
H2A.Z was reduced at the +1 nucleosome (first nucleosome
downstream of the TSS) of memory-promoting genes (Npas4,
Arc, Egr1, Egr2, and Fos), and there was an increase in the
expression of those genes 30 min after the contextual fear
training. In contrast, H2A.Z binding was increased for the
memory-suppressor gene CaN and associated with reduced
expression of this gene. This suggests that H2A.Z at the
+1 nucleosome restricts memory-related gene transcription
[73]. Furthermore, the methylation of the promoter region of
the gene encoding H2A.Z (H2afz) was shown by MeDIP to
be increased 30 min after contextual fear conditioning, when
it was accompanied by reduced H2A.Z protein expression
throughout the hippocampus, whereas the expression levels
of H2A.Z returned to baseline after 2 h [73].
To assess a causal involvement of H2A.Z in memory
consolidation, an adenoassociated virus (AAV) depleting
H2A.Z in the dorsal CA1 region of the hippocampus was
used. This approach improved fear memory 24 h and 30 d
after training compared to a scramble-injected control group.
In contrast, when H2A.Z was depleted from the mPFC,
there was no effect on fear memory at the hippocampusdependent 24 h time point, yet the freezing was significantly
higher at remote time points 7 and 30 days after training
[73]. Moreover, a genome-wide transcriptional analysis was
carried out to evaluate the impact of H2A.Z depletion on
training-induced gene expression in CA1 and mPFC 30 min
after training. The analysis showed a differential expression—
between the trained and untrained groups—in many genes
including a number of the early learning-related genes:
Arc, Fos, Egr1, and Egr2 [73]. Although the study did not
ascertain the specific target genes through which H2A.Z
regulates memory, it clearly demonstrated that H2A.Z is
dynamically regulated during learning and memory and
that it could be an important epigenetic contributor to the
complex coordination of gene expression in memory. Future,
more refined studies will certainly help to elucidate the role of
histone exchange and histone PTM processes associated with
remote memory storage or extinction (Box 2).
5. Summary
The allocation of a memory to a particular neural circuit
is a critical step in memory formation. We reviewed how
CREB is involved in such process highlighting its important
8
Neural Plasticity
In addition to memory formation and storage, a recent study also showed an epigenetic involvement into remote fear memory
attenuation [80]. In this study, permanent attenuation of remote fear memories was achieved by using a histone deacetylase-2
inhibitor (HDAC2i) in combination with reconsolidation-updating paradigms, which increased the acetylation levels of histone
H3K9/14 (AcH3). In contrast to a vehicle-treated control group that was resistant to remote memory attenuation, a significant
increase in AcH3 was noticed 1 h after remote fear memory recall in the ACC, which stayed elevated even after the extinction
training. In the HPC, no change was observed in the acetylation levels of AcH3 1 h after recall, yet a significant increase was seen in
the HDAC2i-treated group after extinction training. More specifically, this observed increase in acetylation in the HDAC2i-treated
group was detected in the promoter region of neuroplasticity-related genes such as cFos, Arc, and Igf2, which showed a concomitant
increase in expression [81]. This clearly displays that attenuating remote fear memories using an HDAC2i promotes increased
histone acetylation-mediated neuroplasticity and in turn demonstrates an epigenetic contribution to this process.
Box 2: Recent insights into epigenetic dynamics of remote memory attenuation.
role. Additionally, electrophysiological studies showed that
cells transfected with CREB viral vectors are more excitable
compared to the neighboring cells or even those transfected
with the control vector [22]. This could partially address
the preference of allocating the memory to CREB cells
since their increased excitability might render them more
responsive to sensory inputs and therefore more likely to
get activated during conditioning training. However, it could
still be possible that there are other molecular determinants
and processes that are important for memory allocation.
Indeed, although CREB is ubiquitously expressed, it seems
unlikely that memory allocation depends solely on this
transcription factor. Likewise, adult neurogenesis is restricted
to only certain brain regions, and the data showing that
new granule cells when mature are increasingly likely to be
incorporated into circuits supporting spatial memory [28, 29]
is not necessarily the sole determinant of allocating a memory
to a specific neural population.
Another important aspect of memory persistence is
which brain regions maintain its storage and what supports
such perseverance. We highlighted the importance of the
ACC in the upkeeping of remote memories since its inactivation prevents the recall of remote contextual fear memory as
well as the reconsolidation of such remote memory 24 h after
its retrieval [46, 49]. Intriguingly, a recent study identified
for the first time monosynaptic projections from the ACC
to the hippocampal CA fields that controls memory retrieval
in mice [75]. Using retrograde tracers, this study characterized novel connections between ACC and CA fields (ACCA) that subserve a potential bidirectional communication
between the ACC and the hippocampus. Manipulating these
projections optogenetically demonstrated a causal top-down
control on memory retrieval, where the cells contributing to
the AC-CA projection can activate contextually conditioned
fear behavior (3-day-old memory), whereas their inhibition
impaired the retrieval of such memory [75]. Nevertheless,
further investigations are still needed to elucidate the role
of these projections on the regulation of different memory
processes.
In fact, the cellular reconsolidation of a remote memory
might not solely depend on the ACC since it has been shown
previously that infusing anisomycin in the dHPC blocks
the reconsolidation of remote contextual fear memory and
that optogenetically inactivating the CA1 region would even
impair recalling it [12]. Contradictorily, another study did
not find any evidence that neither the ACC nor the dHPC is
involved in the cellular reconsolidation of remote contextual
fear memory following retrieval [76]. More studies are highly
anticipated to resolve these divergent findings, although such
discrepancy could be partly attributed to the difference in
the strength and length of the training and retrieval sessions
used or in the inactivation method and its efficiency, since
it has been demonstrated that these experimental conditions
significantly affect the behavioral outcome [10, 77].
Structural plasticity is another key point towards understanding the endurance of some memories. It provides a physical substrate for the storage of memories. We highlighted
the synaptic plasticity that follows memory formation at hippocampal dendrites and that such plasticity reaches cortical
areas in a time-dependent manner [16, 17]. Nonetheless, we
also shed light on two interesting studies supporting the view
of an early cortical reorganization during motor skill learning
[54] as well as episodic memory acquisition [38], which
demonstrated the importance of such structural changes for
lasting memories. The reduced density of spines in cortical
areas upon remote fear extinction is in line with these findings
and suggests remodeling in the cortical circuit of the original
memory [78]. However, a contradicting study showed that it
is rather fear memory formation that is accompanied by spine
elimination and that extinction involves spine formation
[79]. These results are quite confusing, and although they
could also be reflecting that opposite processes are at play in
different cortical areas, they need to be addressed properly
soon.
The epigenetic regulation was the final point we highlighted in this review, and the data we reviewed—collectively—support a dynamic pattern of epigenetic modifications including both DNA methylation [68] and histone
PTMs [71] that subserve a spatiotemporal shift of the memory
trace from the HPC to higher cortical regions during the
process of memory consolidation. Also, the early tagging of
certain neurons with epigenetic marks during encoding is
central for the memory to be allocated to the tagged neurons
and for the subsequent participation of these neurons in
the circuit supporting such memory [45]. Furthermore,
the extinction of remote fear memories with an HDAC2i
increased histone acetylation-mediated neuroplasticity [80],
and the lack of such plasticity from the hippocampus upon
Neural Plasticity
remote memory recall supports the idea of hippocampal disengagement for remote memories [46, 48, 55]. Nevertheless,
whether memories might indeed be “coded in particular
stretches of chromosomal DNA” as originally proposed by
Crick [57] and if so what the enzymatic machinery behind
such changes might be remain unclear. In this regard, cell
population-specific studies are highly warranted.
Taken together, we find ourselves in an exciting period
witnessing an increasing number of studies, which dare to
investigate remote memory formation, storage, and persistence. Yet it is clear that we are still in need of further
investigations to unveil the dynamics of neuronal circuits
and molecular mechanisms mediating such persistence.
Ultimately, deciphering these processes would definitely
contribute to the understanding, and possibly dulling, of
abnormally long-lasting fear memories like those underlying
anxiety disorders or posttraumatic stress disorder.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
Acknowledgments
This work is funded by the Swiss National Science Foundation
(Project Grant 31003A 155898), by the National Center for
Competence in Research (NCCR) SYNAPSY, by the Synapsis
Foundation for Alzheimer Research, by the Béatrice EdererWeber Stiftung, and by an Alzheimer’s Association New
Investigator Research Grant to Johannes Gräff. Johannes
Gräff is an MQ fellow.
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Volume 2014
Volume 2014
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Autism
Neural Plasticity
Research and Treatment
Hindawi Publishing Corporation
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Computational and
Mathematical Methods
in Medicine
Hindawi Publishing Corporation
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Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Neurology
Research International
Hindawi Publishing Corporation
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Volume 2014
Psychiatry
Journal
The Scientific
World Journal
Hindawi Publishing Corporation
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Volume 2014
Hindawi Publishing Corporation
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Cardiovascular Psychiatry
and Neurology
Volume 2014
Neuroscience
Journal
Journal of
Volume 2014
Hindawi Publishing Corporation
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Volume 2014
Hindawi Publishing Corporation
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Volume 2014
Parkinson’s
Disease
Neurodegenerative
Diseases
Hindawi Publishing Corporation
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Epilepsy Research
and Treatment
Volume 2014
BioMed
Research International
Hindawi Publishing Corporation
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Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014